Cyclopentanophenanthrene compounds and process



United States Patent 3,134,791 CYCLOPENTANOPHENANTHRENE COMPOUNDS ANDPROCESS Carl Djerassi and Howard J. Ringold, Mexico City, Mexico,assignors, by mesne assignments, to Syntex Corporation, a corporation ofPanama No Drawing. Filed July 8, 1959, Ser. No. 825,664

Claims priority, application Mexico July 9, 1958 8 Claims. (Cl.260-3974) The present invention relates to cyclopentanophenanthrenederivatives and to a method for preparing the same.

In particular, it relates to the novel 1601-!116ll1Yl-606- halo (fluro,chloro or bromo)-17ot-acyloxy-progesterone, which compounds areeffective progestational agents by the oral or parenteral route, andwhich may be expressed by the following formula:

and comprises also their l-dehydro derivatives which may be expressed bythe following formula:

In both these formulas X represents a halogen selected from the group offluorine, chlorine and bromine, which may be in the aor [i-position, andR represents a hydrocarbon carboxylic acid acyl group of up to 12 carbonatoms, of straight or branched chain, saturated or unsaturated, cyclicor mixed cyclic-aliphatic, substituted or not with functional groups,such as methoxy or halogen for example. Among other (2-17 esters, theremay be the acetate, propionate, butyrate, t-butyrate, hemisuccinate,enanthate, caproate, benzoate, trimethylacetate, phenoxyacetate,phenylpropionate, cyclopentylpropionate and ,6- chloropropionate.

The following equation illustrates a process for preparing the novelcompounds of the present invention:

CH3 a 'I... 3 CH3 ice G H CH (iJH OH; 00

Hon

In the above equation X and R represent the same groups as heretoforeset forth.

In practicing thegprocess as heretofore set forth an ester of16a-methyl-l7a-hydroxy-progesterone (1) disclosed and claimed in US.application Serial No. 773,830, filed November 14, 1958, was used as astarting material.

To prepare the novel 6-chloro and 6-bromo derivatives, the abovecompound was treated with a triester of orthoformic acid in dioxanesolution and in the presence of p-toluenesulfonic acid and there wasobtained a 3- alkyl-enol-ether (II); this compound was treated withhypochlorous acid or hypobromous acid, using for this reaction anyreagent capable of generating such acids, such as N-chloro or N-bromoamides or imides, hypochlorites or hypobromites of alkali or alkalineearth metals; preferably there were used the corresponding N- halosuccinimides in acetone solution and in the presence of acetic acid andsodium acetate. Thus there was produced a 16ozmethyl-6i3-chloro-17ec-acyloxy-progesterone (III; X=fl-chloro) or a l6a-methyl-63-bromo-l7a-acyloxy progesterone (HI; X=B-bromo) respectively, whichwere dehydrogenated between C-1 and 0-2 by microbiological methods, forexample by incubation with species of Corynebacterium simplex, or bymeans of purely chemical methods, such as refluxing with seleniumdioxide in mixture with t-butanol, in the presence of pyridine, under anatmosphere of nitrogen and for a period between 12 and 96 hours, toyield a l6amethyl- 6,8 halo 17cc acyloxy-A -pregnadien-3,20-dione (IV).

Patented May 26, 1964' By treatment with acid under vigorous conditionsthe steric configuration at C-6 was inverted to yield 2.16amethyl-fiot-halo-17a-acyloxy-A -pregnadien-3,20 dione; preferablythis reaction was carried out with dry hydrogen chloride in glacialacetic acid solution, at temperatures around 15 C.

To prepare the novel 6-fluoro derivatives, 16a-methyl-17ot-acyloxy-progesterone was treated with an alkyleneglycol to yield a16ot-methyl-3-alkylenedioxy-l7a-acyloxy- A -pregnen-20-one, preferably16a-methyl-3-ethylenedioxy-17oc-acyloxy-A -pregnen-2O-one (V) byrefluxing with ethylene glycol in mixture with benzene, under anhydrousconditions and in the presence of p-toluenesulfonic acid. The nucleardouble bond of V was epoxidized by reaction with a peracid, for exampleby reaction with monoperphthalic acid in a mixture of ether andchloroform. The resulting 16ot-rnethyl-3-ethylenedioxy-17a-acyloxy-5a,6a-oxido-pregnan-ZO-one (VI) was treated with boron trifluoride in amixture of ether-benzene, at room temperature, and thus there wasproduced the corresponding16a-methyl-3-ethylenedioxy-l7a-acyloxy-6B-fluor0 pregnan-5a-ol-20-one(VII). By reaction with concentrated aqueous hydrochloric acid in aceticacid solution at room temperature, the ketal group was hydrolyzed withsimultaneous dehydration at C-5 to produce the 16ot-methyl- 6fit-fiuoro17oz acyloxy progesterone (III). This compound was dehyd'rogenated withselenium dioxide to form 16u-methyl-6fl-fluoro-17a-acyloxy-A pregnadien3,20- dione (IV; X=fi-fluoro) the steric configuration at C-6 wasinverted to produce 160c-I1'161Zl1Yl-60t-fill010-170L-aCyloxy-A-pregnadien-3,20-dione (IV; X: a-fluoro).

Alternatively, by treatment of the S-hydroxy compound (VII) with dryhydrogen chloride in glacial acetic acid solution at a temperaturearound 15 C. for approximately 4 hours, there was achievedsimultaneously the hydrolysis of the ketal group, the dehydration at C-5as well as the inversion of the atomic configuration at C-6, to yield16a-methyl-6a-fluoro-17a-acyloxy-progesterone. Subsequent refluxing withselenium dioxide produced 16 amethyl 6a fluoro-17a-acyloxy-A-pregnadien- 3,20-dine.

The following specific examples serve to illustrate but are not intendedto limit the present invention.

Example I To a solution of 4 g. of 16a-methyl-17u-acetoxy-progesteronein 28 cc. of anhydrous dioxane there was added 4 cc. of ethylorthoformate and 120 mg. of p-toluenesulfonic monohydrate acid and themixture was stirred for 30 minutes; 10 cc. of pyridine and 400 cc. ofwater were added with stirring and cooling and the reaction product wasextracted with ether, Washed with water, dried over anhydrous sodiumsulfate and evaporated. The residue crystallized from methanol-water togive 16a-methyl-17aacetoxy-3-ethoxy-A -pregnadien-ZO-one.

3 g. of the above compound was dissolved in 90 cc. of acetone, cooled to0 C., mixed with 1.6 g. of anhydrous sodium acetate and 3 g. ofN-chlorosuccinimide followed by 1.5 cc. of glacial acetic acid and themixture was stirred for 3 hours at a temperature between 0 and C. 500cc. of ice water was added and the mixture was kept overnight at 0 C.;the precipitate was collected by filtration, washed with water, driedand recrystallized from ether-acetone containing a few drops ofpyridine. There was thus obtained 16a-methyl-6fl-chloro-l7a-acetoxy-progesterone.

A mixture of 2 g. of 16a-methyl-6p-chloro-17a-acetoxy-progesterone, 100cc. of t-butanol, 0.8 g. of selenium dioxide and 0.4 cc. of pyridine wasrefluxed for 48 hours under an atmosphere of nitrogen and then filteredthrough celite; the filtrate was evaporated under reduced pressure. Theresidue was dissolved in acetone, refluxed with decolorizing charcoalfor 1 hour, filtered through celite, evaporated to dryness and theresidue was purified by chromatography on neutral alumina. There wasthus 4 obtained 16a methyl-6/3-chloro-17a-acetoxy-A -pregnadien-3,20-dione.

1.5 g. of the above compound was dissolved in 75 cc. of glacial aceticacid and a slow stream of dry hydrogen chloride was introduced into thesolution for 4 hours, while the temperature was maintained below 15 C.After pouring into ice Water the precipitate Was filtered andrecrystallized from acetone hexane, thus giving 160;- methyl 6achloro-17a-acetoxy-A -pregnadien-B',20- dione.

Example I] Substituting in the method of the previous example theN-chlorosuccinimide by N-bromosuccinimide, there was obtained, via16a-methyl-6fi-bromo-17a-acetoxyprogesterone and16amethyl-6B-bromo-17a-acetoxy-A -pregnadiene-3,20-dione, the16tZ-H'1CthYl-60t-l3l'0l'l'l0-17d-aC6tOXy- A -pregnadien-3,ZO-dione.

Example III In the previous examples there was changed the order of thereactions: the steric configuration at C-6 of 16amethyl6B-halo-l7a-acetoxyprogesterone was first inverted and the resulting16a-methyl-6a-halo-17-acetoxyprogesterone was dehydrogenated to itsl-dehydro analog.

Example IV In the methods of Examples I-III there was substituted theacetate of the starting material by another ester of any hydrocarboncarboxylic acid having up to 12 carbon atoms and/ or the ethylorthoformate by another ester of orthoformic acid. Specifically, thecaporate of 160:- methyl-17ot-hydroxyprogesterone was treated with ethylorthoformate to obtain l6a-methyl-17ot-caproxy-3-ethoxy-A-pregnadien-2O-one and the latter was converted, by reaction withN-chlorosuccinimide, into 16a-methyl-6fl-chloro-l7a-caproxy-progesterone, whose steric configuration at C-6was inverted by treatment with dry hydrogen chloride in glacial aceticacid solution, and further dehydrogenation of the product afliorded16ot-Inethyl 6m chloro-17u-caproxy-A -pregnadien-3,20-dione. Thecyclopentylpropionate of 16a-methyl-17a-hydroxyprogesterone wasconverted by reaction with the tripropyl ester of orthoformic acid into16a-methyl-17u-cyclopentylpropionoxy 3 propoxy-A -pregnadien-ZO-one,which was treated with N-bromosuccinimide and then with dry hydrogenchloride, to producel6a-methyl-6abromo-17a-cyclopentylpropionoxy-progesterone and then 16ccmethyl-6a-bromo-l7a-cyclopentylpropionoxy-N' pregnadien-3,20-dione.

Example V A mixture of 5 g. of 16a-methyl-l7a-acetoxy-progesterone, 100cc. of anhydrous benzene, 35 cc. of ethylene glycol distilled oversodium hydroxide and 600 mg. of p-toluenesulfonic acid was refluxed for8 hours, with the use of an adapter for the continuous removal of water.The mixture was cooled, washed with aqueous sodium bicarbonate solutionand with water, dried over anhydrous sodium sulfate and evaporated todryness. The residue crystallized from acetone-hexane to give16a-methyl-17uacetoxy-3-ethylenedioxy-A -pregnen-2O-one.

4 g. of the above compound was dissolved in cc. of chloroform, cooled to0 C., mixed with an ether solution of perphthalic acid containing 1.2molar equivalents of the reagent kept in the dark for 16 hours at atemperature between 0 and 5 0., water was added, the organic layer wasseparated and washed with aqueous sodium bicarbonate solution and waterto neutral, dried over anhydrous sodium sulfate and evaporated. Theresidue crystallized from acetone-hexane to furnish 16u-methyl- 17aacetoxy 3-ethylenedioxy-5a,6a-oxido-pregnan-20- one.

To a solution of 3 g. of the above compound in 300 cc. of a mixture ofequal parts of ether and benzene there was added 3 cc. of borontrifluoride etherate and the mixture was kept for 3 hours at roomtemperature, water was added, the organic layer was washed with Water,dried over anhydrous sodium sulfate and evaporated to dryness.Chromatography of the residue on neutral alumina yielded16a-methyl-6fl-fluoro-17u-acetoxy-3-ethylenedioxy-pregnan-Sa-ol-20-one.

To a solution of the above compound in 100 cc. of acetic acid there wasadded 2 cc. of concentrated aqueous hydrochloric acid and the mixturewas kept at room temperature for half an hour and diluted with water;the precipitate was filtered, washed with water, dried andrecrystallized from acetone-hexane, thus producing 16a-methyl-6/3-fiuoro-l7a-acetoxy-progesterone.

By subsequent refluxing with selenium dioxide, in accordance withExample I, there was obtained lfitx-methyl- 6fi-fluoro-l7a-acetox -A-pregnadien-3,20-dione.

Upon subsequent treatment with dry hydrogen chloride there was obtainedthe 60t-lSOI1'1e1' of the latter compound.

Example VI 2 g. ofl6a-methyl-6B-fluoro-17ot-acetoxy-3-ethy1enedioxypregnan-Swol-ZO-one,intermediate compound in the previous example, was treated in glacialacetic acid solution with dry hydrogen chloride, such as has beendescribed in Example I, to producel6a-methyl-6a-fluoro-17a-acetoxyprogesterone, which was thendehydrogenated to 160;- methyl-a-fiuoro-17a-acetoxy-A-pregnadien-3,20-dione.

Example VII In the methods of the Examples V and VI, there wassubstituted the ester of the starting material by an ester of anycarboxylic acid having up to 12 carbon atoms, and/or the ethyleneglycolby another alkyleneglycol. Specifically,16a-methyl-17oz-propionoxyprogesterone was treated with propyleneglycolto produce 16a-methyl-l7a-propionoxy-3- propylenedioxy-A-pregnen-2O-one, which upon reaction with the peracid gave rise to theformation of 16ot-methyl- 17 u-propionoxy-3-propylenedioxy 50:,6ocoxide-pregnan- 6 20-one; treatment of the latter with boron trifluorideafforded16a-methyl-6fi-fluoro-l7a-propionoxy-3-propylenedioxy-5a,6a-oxido-pregnan-5a-ol-20-onewhich was con verted into 16amethyl-6B-fluoro-l7a-propionoxyprogesterone, then into its Get-isomerand finally into the l-dehydro analog of the latter.

We claim:

1. 16a methyl 6-ch1or0-17a-acyloxy-A -pregnen-3,20- dione, wherein theacyloxy group in that of a hydrocarbon carboxylic acid of up to 12carbon atoms.

2. 16a-methyl-6-bromo-17a-acyloxy-A pregnen-3,20- dione, wherein theacyloxy group is that of a hydrocarbon carboxylic acid of up to 12carbon atoms.

3. 16ot-methyl-6a-chloro-17a-acetoxy-A -pregnen 3,20- dione.

4. 16oc-m6tl1Yl-6a-Chl0l'O-17 ot-caproxy-M-pregnen 3,20- dione.

5. 16u-methyl-6-chloro 17a acyloxy-A -pregnadien- 3,20-dione, whereinthe acyloxy group is that of a hydrocarbon carboxylic acid of up to 12carbon atoms.

6. 16a-methyl-6-bromo-l7u-acyloxy A pregnadien- 3,20-dione, wherein theacyloxy group is that of a hydrocarbon carboxylic acid of up to 12carbon atoms.

7. l6a-metl1yl-6a chloro-17oc-acetoxy-A -pregnadien- 3,20-dione.

8. l6ot-rnethyl-6a-chloro-l7oa-caproxy A -pregnadien- 3,20-dione.

References Cited in the file of this patent UNITED STATES PATENTS2,838,496 Babcock et a1. June 10, 1958 2,838,531 Babcock et a1 June 10,1958 2,950,298 Elks et al Aug. 23, 1960 OTHER REFERENCES Ringold et al.:Journal Amer. Chem. Soc. (1959), vol. 81, page 3485 relied on.

1. 16A - METHYL - 6-CHLORO-17A-ACYLOXY-$4-PREGNENE-3,20DIONE, WHEREINTHE ACYLOXY GROUP IN THAT OF A HYDROCARBON CARBOXYLIC ACID OF UP TO 12CARBON ATOMS.
 2. 16A-METHYL-6-BROMO-17A-ACYLOXY-$4 - PREGNEN-3,20DIONE,WHEREIN THE ACYLOXY GROUPS IS THAT OF A HYDROCARBON CARBOXYLIC ACID OFUP TO 12 CARBON ATOMS.